Steroid aldehydes



Patented Dec. 23, 1952 UNITED STATES PATENT OFFICE STEROID ALDEHYDESRobert H. Levin, A Vern McIntosh, Jr., and George ;B. Spero, Kalamazoo,Mich, assignors to The Upjohn Company, Kalamazoo, Mich, a corporation ofMichigan No Drawing. Application October 2, 1947, Slia'l N0. 777,577

15 Claims. (Cl. 260397.4) 1 v v2 The present invention relates tosteroid aldethioes'teis'of lithocholicaci'd (3-hydroxycholamic hydes andto a method for the-production thereacid), of the formula: of. Theinvention is more specifically concerned wlth'certain steroidaldehydesot the formula: H30 CHPOHZAIIPSR s'rcHow -H A wherein STrepresents a pregnane nucleus at- H80 tached to the side-chain at the 20position, and

n is zero, one or'two, and with a method for the production of the saidsteroid aldehydes from steroid thioesters having a side-chain ofcorresponding length.

It is an object of the present invention to prothioesters Q desoxycholicid 3;12-'dihydroxyvide novel steroid aldehydes. A further objectc'holanicecldh of theformulai of the invention is the provision of anovel procm 0 ess for the preparation of-steroid aldehydes from 1130 vv. steroid thioesters. O'ther'objects of the invention 50 j CHGHCHQ"C*SRwill become a-pparent hereinafter.

Members of the new group of compounds have been prepared, isolated, a'ndfound to he .valuable intermediates in the prepdrationof more complexorganic molecules-including certain hormones.

The method ofthepresentinvention essentially com rises desulfurization o:a steroid ,thioester I I to apstemid aldehyde having/me same number ofthioesters of cholic acid (3,7,l2-trihydroxychocarbon atoms mimesidicham H lanic acid), of the formula:

Among thioesters which "may be employed as H C suitable startingmaterials for the preparation HO CH OH I I of thesteroidaldehydesare'thioester. derivatives of the bile acids, e. g.,cholaiiic acid-of :th'evforinula:

and=thioesters of 317,8,12 tetrahyclroxycholanic 40 acid. or theformula:

.1130 CH: w v v H0 ono macm -omn thioester derivatives of(delta-5)'-cholenic acid, of the formula:

Lu cH- O'HzoH2- c-s1t wherein R is a hydrocarbon radical. Likewise,eother'thioesters of unsaturated jbileacids, such asB -hydrOX y-(delta-5) =cho1enic and 3-hydroxy- (delta=5,7)-icholadienic acids, andester or, ether 3 derivatives of the above hydroxy compounds aresuitable starting materials.

Other suitable thioesters are those having one fewer side-chain carbonatom, i. e., the thioesters of nor-cholanic acids, and related compoundshaving substituents as given above in the cholanic The thioesters ofbisnor-cholanic acids have two fewer carbon atoms in the side-chain, e.g.:

O tars,

and these compounds are also suitable starting materials.

Thioesters having the designated side-chains and additional substituentsin the nucleus, such as hydroxyl groups, esters and ether derivatives ofhydroxyl groups, including i-ethers and i-esters; ketones, ketonederivatives, enol ethers and esters of ketones; amines; protected, e.g., as dihalide or hydrohalide, or unprotected double bonds; and halogenatoms, may also be used as starting materials. Some compounds having thementioned substituents have been indicated for the first series, but anycompound having the prescribed pregnane nucleus and the specifiedside-chain, regardless of other nuclear substituents, may be employed.For example, thioesters of 3,6-diketoallocholanic acid,3,11-diketocholanic acid, 3-chloro-(delta 5)-cholenic acid,3-acetoxy-(delta-5)-cholenic acid, 3-methoxy-(delta 5)-nor-cholanicacid, 3,12-diethoxynor-cholanic acid, and 3-acetoxy-(delta' 5)-bisnor-cholenic acid are entirely satisfactory starting materials.Stereoconfiguration of the starting thioester is immaterial, asaldehydes may be produced with facility regardless of the space factor.

The selected steroid acid may be converted to the correspondingthioester by either of two procedures, both of which may proceed throughthe acid chloride. The first (A) involves reaction of the acid halide,e. g., bromide or chloride, with a mercaptan, preferably in the presenceof an acid-binding agent, e. g., pyridine, substituted pyridines,dimethylaniline, quinoline, or an inert organic solvent, e. g., ether,benzene,

' toluene, xylene, or petroleum hydrocarbons, in

the presence of an acid-binding agent, e. g., pyridine, sodiumbicarbonate, magnesium or calcium oxide. The second (B) involvesreaction of the acid chloride with a selected metallic mercaptide, e.g., a lead, zinc, or aluminum mercaptide, in ether, according to thefollowing sequence, as illustrated for an unsubstituted acid:

(I111: HC oH- cm),.ooo11 l solo: -r I or o 0 or),

CH; 0 m0 oH- oHnF J-wi H5O l I RSH(pyrldiue) or PMSR): (ether) OH: H oHoH;)..-o-s1z HsC wherein: n is zero, one or two; and R is a thioalcoholresidue. Either of the procedures are suitable, the first apparentlygiving better yields of crude product, and the second apparentlyyielding a somewhat purer product. The thioesterification may also beaccomplished from the free acid directly, by reaction with a mercaptan,with or Without an esterification, e. g., acidic, catalyst.

The choice of the R radical in the starting thioester is limited only bythe availability of the mercaptan or mercaptide. B. may be an alkylradical, e. g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl,n-octyl, dodecyl, or the like; a cycloalkyl radical, e. g., cyclopentyl,cyclohexyl; a cycloalkylalkyl radical, e. g., cyclohexylmethyl; an arylradical, e. g., phenyl, naphthyl; or an aralkyl radical, e. g., benzylor phenethyl. Unsaturated aliphates and cycloaliphatics may also beemployed, provided the required starting material is available.Substituted hydrocarbon radicals, e. g., chlorobenzyl, nitrophenyl,bromoethyl, aminopropyl, are also satisfactory in the startingthioester.

PROCEDURE A.-MERCAPTAN The acid chloride, usually in an organic solvent,such as anhydrous benzene, toluene, xylene, ether, or petroleumhydrocarbons, is admixed with a selected mercaptan. Equimolarproportions are satisfactory, but an excess of mercaptan may sometimesbe employed to advantage. The reaction mixture is allowed to stand atabout room temperature, 15-30 hours usually being sufficient time forcomplete reaction. Gentle heating sometimes increases reaction rate, butis not usually necessary. Temperature range is usually about zerotoabout 150 degrees .centigtade. The presence of an acid-binding agent isnot essential, but is usually advantageous in increasing the reactionrate. The reaction product may be worked up with water and anforganicsolvent, e. g., ether, aqueous portions extracted, and combined organiclayer .washed with water, dilute alkali, dilutey'aci'd, and finallyagain with water. Aft'er drying the neutral fraction and evaporating thesolvent, .the residual oil may be crystallized from fa suitablesolvent,.e. g., alcohol, .to. yield the desired thioester, usually astable solid.

Mommas-sprain amass. bassinet et tea sol ntisa d d as l 'td meta ie e ep.enaa s eert bi ni bl e t:erri r a- Eq molar proportions aresatisfactory; other ratios may be used if desired. Temperature range isusually about zero to 150 degrees centigrade. The reaction mixture isallowed to stand with occasional swirling, gentle heating if desired.After -30 hours the metallic mercaptideis usually completely converted't'o'tlie metallic chloride, and theffeadtio'ii product may be worked upas in Procedure A.

The thioesters are stable materials which may be converted when ahydroxy groupis present, to an acyloxy derivative or the thioe's'te r.

The following preparations are given to illustrate the preparation ofsuitablestarting thioesters, but are in no way to be construed aslimiting.

PRErARA'rIoN 1.-:BENZY'L 3-ALrH-a,12-nr.rrr.i-DIACETOXY-NOR-THIOOHOLANATE To 1.5 grams (0.0033 mole) of3-alpha,l2-alpha-diacetoxy-nor-cholanic acid was added 6 milliliters(9.8 grams, 0.082 mole) of purified thionyl chloride (Fieser,Experiments in Or anic Chemistry, Part '11, Heath and Co., New York,1941, p. 381). minutes and the solution was allowed to stand, withoccasional swirling, at room temperature for one hour. Twentymilliliters of a 1:1 mixture of anhydrous benzene and ether was thenadded and the whole evaporated to dryness in vacuo at 40 degreescentigrade. This process of treatment with benzene-ether was repeatedtwice to ensure complete removal of excess thionyl chloride.

To the resulting acid chloride dissolved in 10 milliliters of anhydrousbenzene was added 0.4 milliliter (0.005 mole) of dry pyridine and 2milliliters (1.12 grams, 0.009 mole) of benzyl mercaptan, a precipitatesoon forming. After standing for twenty-four hours at room temperature,I

lizfed from tofmilhfte'rs of jrier rent alcohol to give 1.3a r73 cent)erprdduet. 'M. P. rev- 152 degrees centigfade. 'After t reefreieystaiirza'uns 'rreiniaiebuql. 1.23 grams (65.5

percent) 'dftheben'zyl 'thiost'r with a ronstant The acid dissolvedwithin five 6 melting point of 154- 156 degrees centigrade (corn) wasobtained.

Pnsmeerron 2.+ETH'IL 3-AILPHA,12-ALPHA- Drronuoxr-Tiirooriomnnrn Theacid chloride (prepared from 4.5 grams (0.01 mole) of 3-alpha,12alpha-diformoxydesoxycholic acid in the manner described inPreparation 1) wasdissolved 'in 30. milliliters of anhydrous etherandadded to 1.8 grams (0.00.55 mole) of lead ethyl mercaptide'coveredwith 20 milliliters of anhydrous ether. Themixture was allowed to standat rooin 'temperature with occasional swirling, the yellow leadmercaptide being gradually replaced by white lead chloride. Aftertwenty-four hourathe solution was filtered and the precipitate washedwith '50 milliliters of ether. The combined ether filtrate was washedwith milliliters of one gee]: cent aqueous sodium hydroxide solution and300 milliliters of water, then dried over anhydrous sodium sulfate andevaporated to dryness in vacuo on the steam bath. The residual oil wasdissolved in 50 milliliters of hot alcohol and 10 milliliters of wateradded. On cooling, an oil separated, taking with it all the color in thesolution. Crystallization yielded 2.2 grams of material. An additional0.32 gram of crystals was obtained by crystallizing .the oil fromalcohol, the total yie'ldfbeirig 2552 Three grains (0.0076 seatf's-aaaaiy zaaa 5) -cholenic acid was placed inia flf-ml lterjsideinlet flask with'GIO milliliters (0.082-mulel1of thionylchloride and allowed tofsftaiid f frie hour with occasional. shaking.Fifteen mi lliliters of dry ether and benzene -(1:1 was then added, andthe solvent removedinvacuo. The addition and removal of ether-sesamewasrepated three times.

Fifteen milliliters of 'was'added'tothe acid chloride without removaljrrom the "original flask, whereafter 0.011el'ino'lev(0.91'in'illiliter) of pyridine and 0.0380 mole (2.8 milliliters) bfethyl mercaptan was added to the'fbefii'z'ehe 'solution. The reactionmixturewas'alltiwedFtofstand for one day at room temperature'afidwasthenrinsed into a 100-milliliter separatoryfiihfiel with 30 milliliters ofether and'30 milli'l'i'trsof water. The ether-benzene solution wassepar'ated and washed by the procedure of Brcparation 1. Two andfour-tenths grams of ethyl B-acetoxy-(delta- 5) -thiocho l en'ate,melting at 100 to 102 degrees centigrade, was-obtained,the yildbeing73.0 per cent.

PREBABATIQN d -l fl rrrrr gfnosroxr- (Dam-5 riarooiioLiiwi'm(Phoofinti'liit 13) Three rams-raoo'ro noieref 3-acetoxy=('delta- 5)-cholenic acid was placed'lnfa-lill-milliliter sideilfilet flask with6.0 milliliteis101054 mt $16) 0f thionyl chloride and alldvvdto-stand'for one hour with occasional shaking. Fifteen milliliters of dry etherand benae'rie 1:11) was' added-and the solvent removed nmates. Theaddition and removal of ether be riziie was repeated three times.

ride in 20 milliliters of aimydrds etlier'added thereto. The im'xturewas stirred for 4-6 hours and allowed to stand overnight at roomtemperature. The mixture was filtered and insoluble material washed witha few milliliters of ether, the filtrate transferred to a separatoryfunnel and Washed with 50 milliliters of one per cent cold aqueoussodium hydroxide solution and 100 milliliters of water, after which thewater layer was discarded. The ether phase was dried over anhydroussodium sulfate, filtered, and evaporated to dryness. The residue wastaken up in 35 to 40 milliliters of alcohol and cooled. Crystallizationtook place, the material was further cooled in a refrigerator, and thecrystals were separated. One and seven-tenths grams of ethyl3-acetoxy-(delta-5) -thiocholenate, melting at 101-103 degreescentigrade, was obtained.

Other suitable thioesters which may be employed as starting materials inthe method of the present invention are given in the following table:

8 modified Raney nickel catalysts, modified Raney iron catalysts, andother modified "catalysts 'of this type. Preparation of Haney-typecatalysts is known to the art (R. Paul and G. Hilley. Compt. rendus,206,608 (1938); U. S. Patent 2,363,311 to F. W. Breuer; Homer Adkins,Reactions of Hydrogen with Organic Compounds over Copper-Chromium Oxideand Nickel Catalysts, University of Wisconsin Press, Madison 1937 p. Ifsuch normally active Raney-type catalysts are employed, the objects ofthe invention cannot be accomplished as the desired aldehydes are notproduced and the thioesters are quantitatively reduced to alcohols. Ithas now been found that, upon proper modification, a Raney-type catalystis an eifective agent for splitting CS bonds and replacing them with C-Hbonds, and thus suitable for use in the conversion of steroid thioestersto steroid aldehydes in high yields. Such modification may be THIOESTERSOF STEROID ACIDS Analyses, Percent b h Compound M. P.,C.- gigggf 2853 3Carbon Hydrogen sulfur Cale. Found Calcd. Found Calcd. Found ethylS-beta-hydroxy-(delta 5)- thiocholenate 1085-1095 -38.5 CRQHHOXS 74.5974.64 10.00 10.07 7, 779 ethyl 3-beta-iormoxy-(delta 5)- thiocholenate81-82 47.5 CnHuOzS 72.60 72.07 9.48 9.61 7.18 7.01 ethyl3-beta-aoetoxy-(delta 5)- thiocholenate 101.5-103.5 40.9 0771144038 729972.92 9.63 9.69 6.98 7.36 isopropyl 3-heta-acetoxy-(delta 5)-thiocholenate 131-133 40.4 CziHuOJS 73.37 73.39 9.77 9.55 3.75 .3teit-hutyl S-beta-acetoxy-(delta 5)- thiocholenate 169.5-171 39.8CaoHnOaS 73.72 74.07 9.90 9,9 an n-hexyl-B-heta-acetoxy-(delta 5)-thiocholenate 77.5-79.5 35.4 CazHnOaS 74.37 74.70 10.14 10.00 6.20 6.60ethyl-3-chloro-(delta 5)-thiochole- 103.5-105 -30.4 CnHnOSCl 71.44 71.519.46 9.58 8.11 8.75

165-168 CzaHnOaSCl 0.45 0.32

bisnor-thiocholenate 132-133 38.0 OzoHmOzS 72.18 72.50 9.32 9.13 7.417.44 ethyl 3-alpha, 12-diform0xy-thioholanat 111-112 +921 07511405868.25 68.39 9.00 8.89 6.51 6.51 ethyl 3-alpha-iormoxy-th1ochola- 118156"32 +41-3 CnHnOaS 72.27 72.53 9.88 9.74 7.14 7,23 ethyl 3Palpha,l2-d1acetoxy-northiocholanate ill-91.5 +960 0281146053 68.76 69.07 9.159.47 6,33 .3 benzyl 3-alpha, l2-alpha-d1acetoxy-nor-thiocholanate.154-156 +955 CnHisOsS 71.79 71.56 8.51 8.79 5.64 5.66 phenyl 3-alpha,12-alpha-diacetoxy-nor-thiocholanate 146-147 +997 031114058 71.44 71.308.36 8.04 5.78 5.64 phenyl S-beta-acetoxy-(delta 5)- thiocholenate 128.5-130 75.40 75.11 8.90 8.59 6.29 6.89 benzyl 3-beta-acetoxy-(delta 5)-thiocholenate 85-865 75.67 75.77 9.05 8.72 ethyl 3-alpha, 7-alpha,lZ-alphatriformoxythiocholanote c. 128 64.77 64.78 8.44 8.07 ethyl3-alpha-hydroxy-l2-alphaaoetoxythinohnlanata 9. 54 9 34 ethyl3-methoxy-(delta-5)-bisnorthiocholenate 94-96 ethylS-benzoyloxy-(delta-5)-thiocholenate 178-182 ethyl thiodehydrocholate244-246. 5

I All m. p.'s corrected.

7 Rotations taken at approximately C. in chloroform with a 1 cm. tube.Desoxycholic acid is formulated as (talpha, 12-alpha, according to thelatest evidence (Ann. Rev. Biochem. 15, 162 (1946)) Chlorine analysis.

The presence or absence of substituents in the thedimethylcyclopentanopolyhydrophenanthrene nucleus of the startingthioester, such as hydroxy, ester or ether groups convertible to hydroxywith the aid of hydrolysis, halogen, double bonds, and the like, isimmaterial to the present process, as it has been found that sensitivegroups commonly present in the steroid nucleus are stable under theconditions of reaction. The stability, particularly that of a nucleardouble bond, is of considerable value, as any double bonds do notrequire protection during preparation of the aldehyde from thethioester.

Desulfurization agents which may be employed ceptor, e. g., an ethylene,or a carbonyl compound such as a ketone, or an aldehyde. This treatmentmay be advantageously carried out by refluxing the normally activecatalyst with the hydrogen acceptor to modify the catalyst sufiiciently,usually for a period of an hour or more, depending upon its initialcatalytic activity, ratios of catalyst to hydrogen acceptor, et cetera.The modified Raney-type compositions will desulfurize, that is convert aC-S bond to a CH bond, but are not possessive of the reducing activinthe method of the present invention include ity of normally activeRaney-type catalysts, and

thus do not reduce. carbjn l groups or ethylenic inkages. in. the compouds! t eat d-.0 products Acetone hasbeen found especially; suitable formodification ofthe Haney-type catalyst, which, for purposes ofconvenience,'is usually Raneynickel. Any other suitable hydro gnacceptor or. Haney-type. catalyst may. also be. employed, however- Thedesulfurization is conducted conveniently by mixing, together themodified Raney-type catalyst and a selected steroidgthioester. Thereactants are maintained "in contact for aperiod of time sufficient toproduce, desulfurization of the starting thioester, with:productionof-the corresponding; side chain-length aldehyde. Agitation isdesirable for intimatecontact of reactants, and heating is likewiseadvantageous in some instances. The temperature is ordinarily maintainedbetween about *de'grees centigrade and 100' degrees Centigrade, Commonorganic solvents, such as: acetone; alcoholyether, and the like, or any:organic: solvent in which: the thioester is soluble and stable, may beemployed. Likewise, water, or mixtures of water and an organic solvent,are suitable, media, providing efiicient contact of reactants, is,maintained. Product separation is accomplished by removing thedesulfurizing agent and working up the organic product according toconventional procedure.

The preparation of thesteroid aldehyde from a steroid thioester may; beillustrated by the following sequence, wherein a simpleunsubstitutedsteroid nucleus is shown;-

dcsuliurization If desired, characterization of thealdehyde may bereadily accomplished by formation of an aldehyde derivative suchas-theoxime, semicarbazone, or other well-known aldehyde derivatives.

The preparation ofan aldehyde by; desulfuriaation of the thioesterisdescribed in'detailin the following illustrative examples, which,however, arenot tobe construed as limiting.

Example: 1 .-3,1 2- diIZCQtQZUZhTIZQTChOZQZLCLZg23.

A suspension of 10 grams of Haney nickel in 30. milliliters of acetone.was heated under flux f W9. b9 3 lle ififi on m 9 h l 31 2-d ece s -nrhiq h le t i milliliters of acetone, followed" by fr'r'iilliliters ofwater, was added thereto. The mixture was heated under reflux. for 70minutes, then cooled, filtered to remove Raney. nickel, and concentratedin vacuo. The residue. was extracted with ether, the ether solutionwashed with dilute acid, dilute. alkali, and water, after which solventswere removed. The residue was treated with semicarbazide acetateto give0.71 gram of thesemicarbazone of 3,12-diacetoxynor-cholanal-23; M. P.210-226 degrees centigrade. A sample recrystallized several times meltedat 229-2305 degrees centigrade.

Example 2.-3-f0rmyZ- Zith0choZanal-24 One gram of the thioethyl ester of3,-formyl lithocholic, acid was reduced to the aldehyde and isolated asthe semicarbaz one as described above. Theyield of crude semicarbazone,M. P. 182-189 degrees centigrade, was 0.9 6 gram. After twocrystallizations from toluene and methanol, 0.32 gram, melting at215-2165 degrees centigrade. remained.

ANALSIS Calculated C, 70.074; H, 9.727; N, 9.43 Found C, 70.37; H, 9:76;N, 9.50

Thesample meltingv at 215-2165 degrees centigrade, was suspended inether, washed with water, andrecrystallized to give a sample melting at224-227 degrees.

Example 3.3-beta-acetoxy- (deltwE) bisnor-choZenaZ-22 A suspension of 5grams of Raney nickel in 15 milliliters of acetone was heated underreflux for 2 hours, then 0.50.0 gram of ethyl 3-betaacetoxy. (delta 5)bisnor thiocholenate in 10 milliliters of acetone and 8. milliliters ofwater was added. The mixturewas refluxed for twohours, allowed tocoolslightly, and filtered to remove Raney, nickel. Theinickel was.washed with methanol. Crystals. began separating in the filtrate, whichwas placed in the refrigerator for three days; then separated byfiltration. The filtrate was diluted with water, giving 197 milligramsof amorphous powder; M. P. 88-90 degrees centigrade. The amorphouspowder (197 milligrams), 0.20 gram of semicarbazide hydrochloride, 0.3gram of sodium acetate, 8 millilitersof 95 per cent ethanol, and 2.5milliliters of water were heated under reflux, for 2, hours, thereaction mixture cooled and diluted with water to. give 246 milligramsof crystals, M. P. -200 degrees centigrade. Afterseveralcrystallizationsfrom absolute alcohol and water, the melting point roseto 215-218 degrees centigrade.

N L SI Calculated for CzaHssOsNa N, 9.805 Found N, 9.70

The powder, M. P. 88-90 degrees centigrade, was 3-beta-acetoxy-(delta-5), -bisnor -c holenaldehyde, which upon recrystallization meltedat 101-108 degrees centigrade.

Example 4.3-alpha,1Z-aZpha-diformoxrcholanal-24 Standard Raney nickel(20 grams) was added to 60 milliliters ofacetone and heated under refluxwith stirring for two hours. A solution of 2 grams of ethyl3-alpha,l2-alpha-diformoxythiocholanate (Preparation 2)- in 4-0milliliters of acetone and40 millilitersof waterwas then added andrefluxing continued for an additional hour. Catalyst was separated byfiltration and the filtrate concentrated in vacuo to a volume of 50milliliters, then extracted with ether (100 milliliters). The ether wasWashed with 100 milliliters of cold one per cent aqueous sodiumhydroxide solution and one-normal hydrochloric acid, and then with 300milliliters of water. After drying over anhydrous sodium sulfate andevaporating to dryness in vacuo, 1.8 grams of3-alpha,l2-alpha-diformoxycholanal-24 was obtained as a colorless oil.

The oil was dissolved in 80 milliliters of absolute alcohol, and 2 gramsof semicarbazide hydrochloride and 3 grams of sodium acetate in 20milliliters of water added thereto. The solution was refluxed for twohours, cooled, and the product precipitated by addition of 200milliliters of water. The yield was 1.8 grams of the semicarbazone; M.P. 217-220 degrees centigrade after several recrystallizations frommethanol.

The 2,4-dinitrophenylhydrazone was prepared by dissolving 860 milligramsof the crude aldehyde in 70 milliliters of absolute alcohol and adding560 milligrams of 2,4-dinitrophenylhydrazine. The solution was heated toboiling, one milliliter of hydrochloric acid added, refluxing continuedfor 25 minutes, and the concentrate allowed to cool. The yield was 520-milligrams of the 2,4-dinitrophenylhydrazone, melting from 157 to 158degrees centigrade.

Example 5.3-alpha,1Z-aZpha-diformomycholenal-24-(fron'z benzylthz'oester) -24 This compound was also prepared from 4.5 grams of benzyl3-alpha,l2-alpha-diformoxy thiocholanate (Preparation 1) and 40 grams ofmodified Raney nickel in 160 milliliters of acetone and 80 millilitersof water. The yield was 3.72 grams of the aldehyde, which was convertedto the semicarbazone and 2,4-dinitrophenylhydrazone as in Example 4.

Example 5.3-hydroxy-(deZta-5) -cholenal-24 A solution of 555 milligramsof ethyl 3-betahydroxy-(delta-)-thiocholenate, M. P. 100-102 degreescentigrade in a mixture of 15 milliliters of acetone and 5 millilitersof water, was heated under reflux for 1.5 hours with 3 grams of standardRaney nickel which had been modified by heating in acetone under refluxfor 2 hours. The reaction mixture was filtered while hot, and thefiltrate was cooled to zero degrees centigrade. A precipitate formed andwas separated by filtration. The filtrate was diluted with water, giving130 milligrams of a precipitate melting at '45 degrees centigrade. Thiswas treated with 2,4- dinitrophenyl-hydrazine and a few drop-s ofconcentrated hydrochloric acid to give 65.6 milligrams of the3-hydroXy-(delta-5) -cholenal-24 dinitrophenylhydrazone, M. P. 180-187degrees centigrade. After crystallization from chloroform and alcohol,the compound melted at 183- 189 degrees centigrade.

Example 6.-3-acetoxy- (delta-5 -cholenal-24 A solution of 1.00 gram ofthyl 3-beta-acetoxy- (delta-5)-thiocholenate (Preparations 3 and 4) in30 milliliters of acetone and milliliters of water was heated 70 minutesunder reflux over 5.0 grams of standard Raney nickel which had beenmodified by heating in acetone. The reaction mixture was filtered whilehot to remove the Raney nickel, and the filtrate was allowed to stand atroom temperature, whereupon cry tal formed. These were removed byfiltration and the filtrate diluted with three volumes of water. givingapproximately 500 milligrams of a solid melting at -120 degreescentigrade. When 240 milligrams of this precipitate was treated with2,4-dinitrophenylhydrazine, 162 milligrams of thedinitrophenylhydrazine, M. P., 176-184 degrees" centigrade, wasobtained. After chromatograph-- ing and crystallization from aceticacid, the di-- nitrophenylhydrazone melted at 184-188 degreescentigrade.

the same conditions.

the preceding examples.

Other aldehydes which may be prepared ac-- cordin to themethod of thepresent invention.

are the following:

Aldehyde LI P., O.

fi-mothoxy-i-bisnor-cholenal-22 scmiearbazonc 188-190.3-methoxy-(delta-5)-blsnor-chclonal-22 semicarbazone. 204-200. 3-hydrox-(delta-5)-bisnor-cholenal-22 semicarbazone. 241-242.3-b1enzoyoxy-(delta-5)-cho1enal-24 dinitrophenylhy- 232.5233.5.

rezone The novel compounds of the present invention have the formula:

in which A is a hydroxyl or acyloxy radical, n is the integer 1 or 2,the 56 bond is either a double bond or a double bond that has beenconverted to a single bond by addition of two atoms of a halogen or onemolecule of a hydrogen halide.

Corresponding steroid aldehydes in which n:(), which are exemplified by3-beta-acetoxy-(delta- 5) -bisnor-cholenal-22 (also designated3-acetoxy-5-ternorcholenyl formaldehyde) that is disclosed in Example ,3herein, are claimed in and may also be prepared by procedures that aredescribed in the copending application of Frederick W. Heyl and AlbertP. Centolella, Serial No. 159,376, filed May 1, 1950, which is acontinuation in-part of their application Serial No. 737,736, filedMarch 27, 1947.

Other representative aldehydes within the scope of the present inventionare:

3 -hydroxy- (delta-5) nor-cholenal-23, 3-propionoXy-(de1ta-5)-cholenal-24, 3-propionoxy-5,6-dichloro-cholanal-24, and 3-formoxy-(delta-5) -nor-cholenal-23.

The 3-acyl group may be varied widely, and may be, for example, formoxy,acetoxy, propionoxy, butyroxy, benzoxy (CeHsCOO, also called'benzoyloxy), and the like.

Various modifications may be made in the 'present invention withoutdeparting from the spirit or scope thereof, and it is to be understoodthat We limit ourselves only as defined inthe appended cla ms- 13 Weclaim: 1. A process for the production of a steroid aldehyde having theformula in which ST represents a steroid nucleus of the group consistingof pregnane, pregnene, and pregnadiene nuclei attached to the side-chainthrough the carbon atom at the 20 position of the steroid nucleus and nis an integer of the group consisting of 0, 1 and 2, which comprises thede sulfurization of a thioester of a steroid acid having the formula inwhich ST and n have the significance assigned above and R is a residueof a thioalcohol, by reaction of the thioester with a substantialproportion of a Raney-type metal catalyst that has been modified bytreatment with a hydrogen acceptor of the group consisting of compoundscontaining carbon-carbon double bonds and compounds containingcarbon-oxygen double bonds, and subsequently recovering the steroidaldehyde from the reaction mixture.

2. A process as defined in claim 1 in which the desulfurization agent isa modified Raney nickel.

3. A process. as defined in claim 1 in which the desulfurization agentis a Raney nickel modified by treatment with acetone.

4. A process as defined in claim 1 in which the desulfurization reactionis conducted at a temperature between approximately 15 and approximately100 degrees centigrade.

5. A process as defined in claim 1 in which desulfurization reaction isconducted in a solvent medium.

6. A process for the production of a steroid aldehyde having the formulas 'roH2)..t JH

in which ST represents a steroid nucleus of the group consisting ofpregnane, pregnene and pregnadiene nuclei attached to the side-chainthrough the carbon atom at the 20 position of the steroid nucleus and nis an integer of the group consisting of 0, 1 and 2, which comprisesmixing together, in the presence of an organic solvent, a thioester of asteroid acid having the formula in which ST and n have the significanceassigned above and R is a thioalcohol residue, with a substantialproportion of a Raney-type metal catalyist that has been modified bytreatment with a hydrogen acceptor of the group consisting of compoundscontaining carbon-carbon double bonds and compounds containingcarbon-oxygen double bonds, at a temperature between approximately 15and approximately degrees centigrade, and subsequently recovering thesteroid aldehyde from the reaction mixture.

7. A process as defined in claim 6 in which the desulfurization agent isa Raney nickel modified by treatment with acetone.

8. A process as defined in claim 6 in which the starting thioester is anester of a thiocholanic acid.

9. A process as defined in claim 6 in which the starting thioester is anester of a (delta-5) -thiocholenic acid.

10. A process as defined in claim 6 in which the starting thioester is a3-hydroxy-(delta-5) -thiocholenate.

11. A process as defined in claim 6 in which the starting thioester is a3-acetoxy-(delta-5)-thiocholenate.

12. A (delta-5)stero-id aldehyde having the formula CH: on, o

oH-uz- -H CH: /\I

in which A is a radical of the group consisting of hydroxyl and radicalsof the formula AcO, wherein Ac is the radical of an unsubstitutedcarboxylic organic acid containing up to and including seven carbonatoms, inclusive, and R is an alkylidene radical having fewer than threecarbon atoms.

13. S-acetoxy- (delta-5) -cholenal-24. 14. 3-hydroxy-(delta-5)-cholenal-24. 15. 3-benzoyloxy-(delta-5) -cholenal-24. A

ROBERT H. LEVIN. A VERN McINTOSH, JR. GEORGE B. SPERO.

No references cited.

1. A PROCESS FOR THE PRODUCTION OF A STEROID ALDEHYDE HAVING THE FORMULA